Diphenols are monomeric starting materials for polycarbonates, polyiminocarbonates, polyarylates, polyurethanes, and the like. Commonly owned U.S. Pat. Nos. 5,099,060 and 5,198,507 disclose amino acid-derived diphenol compounds, useful in the polymerization of polycarbonates and polyiminocarbonates. The resulting polymers are useful as degradable polymers in general and as tissue-compatible bioerodible materials for medical uses, in particular. The suitability of these polymers for their end use application is the result of their polymerization from diphenols derived from the naturally occurring amino acid, L-tyrosine. The disclosures of U.S. Pat. Nos. 5,099,060 and 5,198,507 are hereby incorporated by reference. These previously-known polymers are strong, water-insoluble materials that can best be used as structural implants.
The same monomeric L-tyrosine derived diphenols are also used in the synthesis of polyarylates as described in commonly owned U.S. Pat. No. 5,216,115 and in the synthesis of poly(alkylene oxide) block copolymers with the aforementioned polycarbonates and polyarylates, which is disclosed in commonly owned U.S. Pat. No. 5,658,995. The disclosures of U.S. Pat. Nos. 5,216,115 and 5,658,995 are also hereby incorporated by reference.
Commonly owned International Application No. WO 98/36013 discloses dihydroxy monomers prepared from xcex1-, xcex2- and hydroxy acids and derivatives of L-tyrosine that are also useful starting materials in the polymerization of polycarbonates, polyiminocarbonates, polyarylates, and the like. The preparation of polycarbonates, polyarylates and polyiminocarbonates from these monomers is also disclosed. The disclosure of International Application No. WO 98/36013 is also hereby incorporated by reference.
Synthetic, degradable polymers are currently being evaluated as medical implants in a wide range of applications, such as orthopedic bone fixation devices, drug delivery systems, cardiovascular implants, and scaffolds for the regeneration/engineering of tissue. Such polymers, when used as implants, are non-traceable without invasive procedures. A radio-opaque polymer would offer the unique advantage of being traceable via routine X-ray imaging. The fate of such an implant through various stages of its utility could be followed without requiring invasive surgery.
Davy et al., J. Dentist., 10(3), 254-64 (1982), disclose brominated derivatives of poly(methyl methacrylate) that are radio-opaque. Copolymerization with non-brominated analogs was required to obtain the thermomechanical properties required for its desired use as a denture base. Only in a small range of certain percentage concentrations of the bromo-derivative does the material exhibit acceptable thermomechanical properties. In addition, there is no disclosure that the materials exhibiting acceptable properties remain biocompatible following the addition of bromine to the polymer structure. In contrast to the polymers disclosed in this application, the brominated poly(methyl methacrylates) do not degrade. However, because the bromine atoms are located on the aliphatic ester side chain, upon side chain ester cleavage, the polymer loses its radio-opacity.
Horak et al., Biomater. 8, 142-5 (1987), disclose the triiodobenzoic acid ester of poly(2-hydroxyethyl methacrylate) to be useful as a radio-opaque X-ray imaging marker compound. The iodine content was reported to affect the contrast, volume, mechanical properties and hydrophobicity of the polymer. A proper balance of properties, including radio-contrast and swellability, was achieved through optimization of the iodine content. Again, this material does not degrade through the main chain and loses radio-opacity upon side chain ester cleavage because the iodine atoms are located on the ester side chain.
Cabasso et al., J. Appl. Polym. Sci., 38, 1653-66 (1989), disclose the preparation of a radio-opaque miscible polymer coordination complex of poly(methyl methacrylate) and a uranium salt, uranyl nitrate. The polymer does not degrade through the main chain and the biocompatibility of the uranyl nitrate complex is not reported, nor has the long-term stability of the complex in vivo been established.
Cabasso et al., J. Appl. Polym. Sci., 4, 3025-42 (1990), discloses the preparation of radio-opaque coordination complexes of bismuth bromide and uranyl hexahydrate with polymers prepared from acrylated phosphoryl esters containing 1,3-dioxalane moieties derived from polyols such as glycerol, D-mannitol, D-sorbitol, pentaerythritol and dipentaerythritol. The phosphoryl group was selected to provide stronger coordinating sites for the bismuth and uranium salts and to impart adhesive properties toward hard tissues. Preliminary biocompatibility data indicated satisfactory performance, but the polymer does not degrade through the main chain and the long-term stability of the complex in vivo is not reported.
Jayakrishnan et al., J. Appl. Polym. Sci 44, 743-8 (1992), discloses radio-opaque polymers of triiodophenyl methacrylate and of the iothalamic ester of 2-hydroxyethyl methacrylate. Polymers of useful molecular weight were not obtained, attributable to the presence of bulky iodine atoms in the monomer side chain. It was possible to obtain copolymers with non-iodinated analogs in the presence of crosslinking agents, such that up to 25% of the iodinated monomer could be incorporated. Preliminary biocompatibility data indicated that the presence of triiodophenyl methacrylate caused blood hemolysis. In addition, the materials also do not degrade through the main chain, and in the event of side chain ester cleavage, would lose their radio-opacity because of the iodine atoms being located in the side chain.
Kraft et al., Biomater., 18, 31-36 (1997), discloses the preparation of radio-opaque iodine-containing poly(methyl methacrylates). The monomers were ortho- and para-iodo and 2,3,5-triiodobenzoic acid esters of 2-hydroxymethyl methacrylate, and the para-iodophenol ester of methyl methacrylic acid. The monomers were copolymerized with one or more non-iodinated analogs and a small amount of crosslinkers to produce polymer hydrogels with varying iodine contents. It was reported that the hydrogels were well tolerated by subcutaneous tissues and that the presence of iodine did not severely alter the swellability of the hydrogel. No tissue necrosis, abscess formation or acute inflammation was observed, although all implants were surrounded by a fibrous capsule. However, these materials also do not degrade through the main polymer chain, and upon side chain ester cleavage, lose radio-opacity because of the iodine atoms being located in the ester side chain.
Currently, no technology is available to provide radio-opaque polymers that degrade through the main polymer chain, such as the above-discussed tyrosine-derived polymers. For their intended use as medical implants, radio-opaqueness is a valuable property. A need exists for radio-opaque polymers that degrade through the main polymer chains, such as the tyrosine-derived polymers discussed above.
These needs are met by the present invention. It has now been found that iodination or bromination of the aromatic rings of dihydroxy monomers renders the resulting polymers radio-opaque. Significantly, the resulting polymers exhibit good mechanical and engineering properties while degrading into relatively non-toxic products after implantation in vivo.
In general, the ability of a species to absorb X-rays is related directly to atomic number and is approximated by the relationship.
m=kl3Z4+0.2
wherein m is the absorption coefficient, l is the wavelength of the incident X-ray, Z is the atomic number of the absorbing species and k is the proportionality constant. Iodine and bromine atoms, because of their high mass, scatter X-rays and impart radio-opaqueness. This is highly significant and allows clinicians to visualize any implanted device prepared from a radio-opaque polymer by simple X-ray imaging.
Thus, iodinated and/or brominated derivatives of dihydroxy monomers may be prepared and polymerized to form radio-opaque polycarbonates and polyarylates. These monomers may also be copolymerized with poly(alkylene oxides) and other dihydroxy monomers. In addition, the iodinated and brominated dihydroxy monomers can be employed as radio-opacifying, biocompatible non-toxic additives for other polymeric biomaterials.
Therefore, according to one aspect of the present invention, a diphenolic radio-opacifying, biocompatible, non-toxic additive for polymeric biomaterials is provided having the structure of Formula I: 
Formula I represents a diphenol compound substituted with at least one bromine or iodine atom, wherein each X1 and X2 is independently an iodine or bromine atom, Y1 and Y2 are independently between zero and two, inclusive, and R9 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms. Preferably, R9 contains as part of its structure a carboxylic acid group or a carboxylic acid ester group, wherein the ester is selected from straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms in addition to the rest of the R9 structure, and ester derivatives of biologically and pharmaceutically active compounds covalently bonded to the diphenol, which are also not included among the carbons of R9. R9 can also contain non-carbon atoms such as iodine, bromine, nitrogen and oxygen.
In particular, R9 can have a structure related to derivatives of the natural amino acid tyrosine, cinnamic acid, or 3-(4-hydroxyphenyl) propionic acid. In these cases, R9 assumes the specific structure shown in Formula II: 
R0 is selected from (xe2x80x94CHxe2x95x90CHxe2x80x94), (xe2x80x94CHJ1xe2x80x94CHJ2xe2x80x94) and (xe2x80x94CH2xe2x80x94)d and R4 is selected from (xe2x80x94CHxe2x95x90CHxe2x80x94), (xe2x80x94CHJ1xe2x80x94CHJ2xe2x80x94) and (xe2x80x94CH2xe2x80x94)a, in which a and d are independently 0 to 8, inclusive, and J1 and J2 are independently Br or I. Z is H, a free carboxylic acid group, or an ester or amide thereof Z preferably is a pendent group having a structure according to Formula IV: 
wherein L is selected from hydrogen and straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and derivatives of biologically and pharmaceutically active compounds covalently bonded to the dihydroxy compound.
Z can also be a pendent group having a structure according to Formula IVa: 
wherein M is selected from xe2x80x94OH, xe2x80x94NHxe2x80x94NH2, xe2x80x94Oxe2x80x94R10xe2x80x94NH2, xe2x80x94Oxe2x80x94R10xe2x80x94OH, xe2x80x94NHxe2x80x94R10xe2x80x94NH2, xe2x80x94NHxe2x80x94R10xe2x80x94OH, 
a C-terminus protecting group and a derivative of a biologically or pharmaceutically active compound covalently bonded to the pendent functional group by means of amide bond, wherein in the underivatized biologically of pharmaceutically active compound a primary or secondary amine is present in the position of the amide bond in the derivative.
Z can also be a pendent group having a structure represented by Formula IVb: 
wherein M is a derivative of a biologically or pharmaceutically active compound covalently bonded to the pendent functional group by means of R3, wherein R3 is a linkage selected from xe2x80x94NHxe2x80x94NHxe2x80x94 in the case when in the underivatized biologically or pharmaceutically active compound an aldehyde or ketone is present at the position links to the pendent functional groups by means of R3; and xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94R10xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94R10xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94R10xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94R10xe2x80x94Oxe2x80x94 in the case when in the underivatized biologically or pharmaceutically active compound a carboxylic acid is present in the position linked to the pendent functional group by means of R3; and 
in the case when in the underivatized biologically or pharmaceutically active compound a primary or secondary amine or primary hydroxyl is present in the position linked to the pendent functional group by means of R3.
R10 is selected from alkyl groups containing from 2 to 6 carbon atoms, aromatic groups, xcex1-, xcex2-, xcex3- and xcfx89-amino acids and peptide sequences.
According to another aspect of the present invention, a radio-opacifying, biocompatible, non-toxic dihydroxy additive for polymeric biomaterials is provided having the structure of Formula III: 
Formula III represents a dihydroxy compound substituted with at least one bromine or iodine atom and having a structure related to derivatives of tyrosine joined by way of an amide linkage to an xcex1-, xcex2- or xcex3-hydroxy acid or derivative thereof. Each X2 is independently an iodine or bromine atom; Y2 is 1 or 2; R5 and R6 are each independently selected from H, bromine, iodine and straight and branched alkyl groups having up to 18 carbon atoms; R0 is (xe2x80x94CH2xe2x80x94)d, xe2x80x94CHxe2x95x90CHxe2x80x94 or (xe2x80x94CHJ1xe2x80x94CHJ2xe2x80x94) and R15 is (xe2x80x94CH2xe2x80x94)m, xe2x80x94CHxe2x95x90CHxe2x80x94 or (xe2x80x94CHJ1xe2x80x94CHJ2xe2x80x94), wherein J1 and J2 are independently Br or I and d and m are independently between 0 and 8, inclusive. Z is the same as described above with respect to Formula II.
According to another aspect of the present invention, radio-opaque biocompatible polymers are provided having monomeric repeating units defined in Formulae Ia and IIIa: 
Formula Ia represents a diphenolic unit wherein X1, X2, Y1, Y2 and R9 are the same as described above with respect to Formula I. Formula IIa represents an aromatic dihydroxy unit wherein X2, Y2, R0, R5, R6, R15 and Z are the same as described above with respect to Formula III.
Copolymers in accordance with the present invention have a second dihydroxy unit defined in Formulae Ib or IIIb. 
In the diphenolic subunit of Formula Ib, R12 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms, preferably substituted with a pendent free carboxylic acid group or an ester or amide thereof , wherein the ester or amide is selected from straight and branched alkyl and alkylaryl esters containing up to 18 carbon atoms, in addition to the rest of the R12 structure, and derivatives of biologically and pharmaceutically active compounds covalently bonded to the polymer, which are also not included among the carbons of R12. R12 can also contain non-carbon atoms such as nitrogen and oxygen. In particular, R12 can have a structure related to derivatives of the natural amino acid tyrosine, cinnamic acid, or 3xe2x80x2(4xe2x80x2-hydroxyphenyl) propionic acid.
For derivatives of tyrosine, 3xe2x80x2(4xe2x80x2-hydroxyphenyl) propionic acid and cinnamic acid, R12 assumes the specific structure shown in Formula II in which R0 is xe2x80x94CHxe2x95x90CHxe2x80x94 or (xe2x80x94CH2xe2x80x94)d and R4 is xe2x80x94CHxe2x95x90CHxe2x80x94 or (xe2x80x94CH2xe2x80x94)a, in which a and d are independently 0 to 8, inclusive. Z is the same as described above with respect to Formula II.
In the dihydroxy subunit of Formula IIIb, R16 and R17 are each independently selected from H or straight or branched alkyl groups having up to 18 carbon atoms; R18 is xe2x80x94CHxe2x95x90CHxe2x80x94 or (xe2x80x94CH2xe2x80x94)d and R19 is xe2x80x94CHxe2x95x90CHxe2x80x94 or (xe2x80x94CH2xe2x80x94)c, in which d and e are independently between 0 and 8, inclusive. Z is again the same as described above with respect to Formula II.
Some polymers of this invention may also contain blocks of poly(alkylene oxide) as defined in Formula VII. In Formula VII, R7 is independently an alkylene group containing up to 4 carbon atoms and k is between about 5 and about 3,000.
xe2x80x94(Oxe2x80x94R7)kxe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(VII)
A linking bond, designated as xe2x80x9cAxe2x80x9d is defined to be either 
wherein R8 is selected from saturated and unsaturated, substituted and unsubstituted alkyl, aryl and alkylaryl groups containing up to 18 carbon atoms. Thus, polymers in accordance with the present invention have the structure of Formulae VIII and VIIIa: 
In both formulae, f and g are the molar ratios of the various subunits. The range of f and g can be from 0 to 0.99. It is understood that the presentation of both formulae is schematic and that the polymer structures represented are true random copolymers where the different subunits can occur in any random sequence throughout the polymer backbone. Formulae VIII and VIIIa provide a general chemical description of polycarbonates when A is 
Formulae VIII and VIIIa provide a general description of polyarylates when A is 
Furthermore, several limiting cases can be discerned: When g=0, the polymer contains only iodine or bromine-substituted monomeric repeating units. If g is any fraction greater than 0 but smaller than 1, a copolymer is obtained that contains a defined ratio of monomeric repeating units substituted with bromine or iodine and monomeric repeating units that are bromine- and iodine-free.
If f=0, the polymer will not contain any poly(alkylene oxide) blocks. The frequency at which poly(alkylene oxide) blocks can be found within the polymer backbone increases as the value of f increases.
The radio-opaque bromine- and iodine-substituted dihydroxy compounds of the present invention meet the need for biocompatible biodegradable additives that are miscible with radio-opaque polymeric biomaterials and enhance the radio-opacity of the polymeric materials. Therefore, the present invention also includes the radio-opaque bromine- and iodine-substituted dihydroxy compounds of the present invention, physically admixed, embedded in or dispersed in a biocompatible biodegradable polymer matrix. Preferably, the dihydroxy compound is an analogue of a monomeric repeating unit of the matrix polymer.
The bromine- and iodine-containing polymers of the present invention also meet the need for radio-opaque processible biocompatible biodegradable polymers, the radio-opacity of which is not affected by anything other than degradation of the main polymer chain. Therefore, the present invention also includes implantable medical devices containing the radio-opaque polymers of the present invention. The radio-opaque polymers of the present invention thus find application in areas where both structural solid materials and water-soluble materials are commonly employed.
Polymers in accordance with the present invention may be prepared having good film-forming properties. An important phenomena observed for the polymers of the present invention having poly(alkylene oxide) segments is the temperature dependent face transition of the polymer gel or the polymer solution in aqueous solvents. As the temperature increases, the gel of the polymers undergo a face transition to a collapsed state, while polymer solutions precipitate at a certain temperature or within certain temperature ranges. The polymers of the present invention having poly(alkylene oxide) segments, and especially those that undergo a phase transition at about 30xc2x0 to 40xc2x0 C. on heating can be used as biomaterials for drug release and clinical implantation materials. Specific applications include films and sheets for the prevention of adhesion and tissue reconstruction.
Therefore, in another embodiment of the present invention, radio-opaque poly(alkylene oxide) block copolymers of polycarbonates and polyarylates may be formed into a sheet or a coating for application to exposed injured tissues for use as barrier for the prevention of surgical adhesions as described by Urry et al., Mat. Res. Soc. Symp. Proc., 292, 253-64 (1993). Placement of the radio-opaque polymer sheets of the present invention may be followed by X-ray imaging without invasive surgery. This is particularly useful with endoscopic surgery. Therefore, another aspect of the present invention provides a method for preventing the formation of adhesions between injured tissues by inserting as a barrier between the injured tissues a sheet or a coating of the radio-opaque poly(alkylene oxide) block copolymers of polycarbonates and polyarylates of the present invention.
The poly(alkylene oxide) segments decrease the surface adhesion of the polymers of the present invention. As the value of f in Formulae VIII and VIIIa increases, the surface adhesion decreases. Polymer coating containing poly(alkylene oxide) segments according to the present invention may thus be prepared that are resistant to cell attachment and useful non-thrombogenic coatings on surfaces in contact with blood. Such polymers also resist bacterial adhesion in this, and in other medical applications as well. The present invention therefore includes blood contacting devices and medical implants having surfaces coated with the polymers of Formulae VIII and VIIIa in which f is greater than 0. The surfaces are preferably polymeric surfaces. Methods according to the present invention include implanting in the body of the patient a blood-contacting device or medical implant having a surface coated with the above-described polymers of the present invention containing poly(alkylene oxide) segments.
Blood contacting or implantable medical devices formed from the polymers of the present invention are also included in the scope of the present invention as well. Such polymers may or may not have poly(alkylene oxide) segments.
The present invention also includes microspheres of the radio-opaque polymers of the present invention, useful as X-ray contrast agents or as drug delivery systems, the location of which can be traced by X-ray imaging. For purposes of the present invention, the term xe2x80x9cX-ray imagingxe2x80x9d is defined as including essentially any imaging technique employing X-rays, including the extensively practiced procedures of radiography, photography and Computerized Axial Tomography Scans (CAT scans). Methods in accordance with the present invention for the preparation of drug delivery systems can also be employed in the preparation of radio-opaque microspheres for drug delivery.
In another embodiment of the present invention, the polymers are combined with a quantity of a biologically or pharmaceutically active compound sufficient for effective site-specific or systemic drug delivery as described by Gutowska et al., J. Biomater. Res., 29, 811-21 (1995), and Hoffman, J. Controlled Release 6, 297-305 (1987). The biologically or pharmaceutically active compound may be physically admixed, embedded in or dispersed in the polymer matrix as if it were not a radio-opaque polymer, eliminating the need for radio-opaque filler materials, thereby increasing the drug loading capacity of the matrix polymer.
Another aspect of the present invention provides a method for site-specific or systemic drug delivery by implanting in the body of a patient in need thereof an implantable drug delivery device containing a therapeutically effective amount of a biologically or pharmaceutically active compound in combination with a radio-opaque polymer of the present invention. As noted above, derivatives of biologically and pharmaceutically active compounds can be attached to the polymer backbone by covalent bonds, which provides for the sustained release of the biologically or pharmaceutically active compound by means of hydrolysis of the covalent bond with the polymer backbone.
By varying the value of f in the polymers of Formulae VIII and VIIIa, the hydrophilic/hydrophobic ratios of the polymers of the present invention can be attenuated to adjust the ability of the polymer coatings to modify cellular behavior. Increasing levels of poly(alkylene oxide) inhibits cellular attachment, migration and proliferation, increasing the amount of pendent free carboxylic acid group promotes cellular attachment, migration and proliferation. Therefore, according to yet another aspect of the present invention, a method is provided for regulating cellular attachment, migration and proliferation by contacting living cells, tissues, or biological fluids containing living cells with the polymers of the present invention.
A more complete appreciation of the invention and many other intended advantages can be readily obtained by reference to the following detailed description of the preferred embodiment and claims, which disclose the principles of the invention and the best modes which are presently contemplated for carrying them out.